1. Field of the Invention
The present invention relates to methods of producing optically active diphenylalanine compounds, which are useful as synthetic intermediates for anti-HIV drugs, dipeptidyl peptidase inhibitors, and the like. The present invention also relates to diastereomeric salts of the compounds, which are useful for the production of the compounds.
2. Discussion of the Background
Optically active diphenylalanine compounds (including amino group-protected compounds thereof) are useful as synthetic intermediates for pharmaceutical compounds and, for example, used as synthetic intermediates for anti-HIV drugs (see, e.g., WO04/056764 and U.S. Pat. No. 6,632,816) and dipeptidyl peptidase inhibitors (see, e.g., WO03/002531 and U.S. Patent Publication Nos. 2004/0167341 and 2004/0242636).
As the production method of optically active 3,3-diphenylalanine, a method shown in the following reaction scheme is described, which includes reacting N-(diphenylmethylene)glycine ester (synthesized from benzophenoneimine and glycine ester) and diphenylbromomethane to synthesize a racemate of 3,3-diphenylalanine, forming a diastereomeric salt of the racemate with cinchonidine and performing an optical resolution (see, U.S. Pat. No. 5,198,548). As a result of experimental reproduction of the optical resolution method by the present inventors and the like, however, it was found that the optical purity of the obtained D-3,3-diphenylalanine was 86% e.e.

As a different method, HETEROCYCLES, vol. 57, no. 6, pp. 1143-1148 (2002) and Tetrahedron Letters, vol. 33, no. 23, pp. 3293-3296 (1992) describe asymmetric synthesis methods of N-Boc-diphenylmethylalanine. However, these methods involve the use of a stoichiometric amount of an asymmetric source, and require many steps, a low temperature reaction vessel for the reaction at −78° C. and expensive reagents such as KHMDS and the like, thus leading to high costs. Hence, these methods are hardly industrially advantageous.
Thus, there remains a need for an efficient and low-cost method for producing optically active diphenylalanine compounds. There also remains a need for intermediates which are useful for the production of optically active diphenylalanine compounds.